Hepatocyte growth factor (HGF) is a secreted, heparin-binding protein that stimulates mitogenesis, motogenesis, and morphogenesis in a wide spectrum of cellular targets. Its receptor is the receptor tyrosine kinase (RTK) c-Met. Activation of the HGF/c-Met signaling pathway leads to a variety of cellular responses, including proliferation and survival, angiogenesis, and motility and invasion. Ma et al., Cancer and Metastasis Reviews 22: 309-325, 2003. Overexpression of c-Met and uncontrolled activation of its signaling pathway occurs in many human cancers. The presence of increased expression of either c-Met or HGF in tumor cell lines has been shown to correlate with tumor aggressiveness and decreased survival rates in several types of cancer. Wang et al., Molecular Cancer Therapeutics 2: 1085-1092, 2003.
The overall structure of the c-Met receptor (FIG. 1) is that of a typical RTK, with an extracellular ligand binding domain, a transmembrane helix, and an intracellular kinase domain. HGF binding to the extracellular domain promotes receptor dimerization and the autophosphorylation of several tyrosine residues in the kinase domain, leading to kinase activation. Ma et al., Cancer and Metastasis Reviews 22: 309-325, 2003. As shown in FIG. 1A, the intracellular domain has a typical kinase fold, with a β-sheet-containing lobe and a helical lobe connected through a hinge region. The ATP binding site (FIG. 1B), is in a deep, narrow, coin-slot-like cleft between the two lobes. Schiering et al., Proceedings of the National Academy of Sciences USA 100: 12654-12659, 2003. Germline and somatic missense mutations in the kinase domain of c-Met, leading to increased kinase activity, have been found in papillary renal cell carcinomas and in cancers of the lung, thyroid and head and neck. This suggests that selective inhibition of the kinase domain may be a viable therapeutic strategy for the treatment of papillary renal carcinoma and possibly several other human cancers. Most existing kinase domain inhibitors target the ATP binding site. It was originally thought that identifying inhibitors selective to only one kinase domain would be difficult, since there are many kinases, all of which bind ATP, and the sequence of residues in the ATP binding site is highly conserved. However, in contrast to this original belief, in recent years selective kinase inhibitors have been developed. Gould et al., Pharmacology & Therapeutics 93: 169-178, 2002; Noble et al., Science 303: 1800-1805, 2004; Bellon et al., J. Biol. Chem. 283: 2675-2683, 2008; Kim et al., Abstract MEDI-361 at 234th National American Chemical Society Meeting, Boston, Mass., Aug. 19-23, 2007. Despite the availability of selective kinase inhibitors, a need exists in the art for developing improved therapeutic compositions for treatment of cancer related to mutations in the c-Met kinase domain.